Process for the preparation of (±) 1-3-dioxolanes and the optical resolution thereof

ABSTRACT

(±) 3-(4-Phenyl-1-piperazinyl)-1,2-propanediol cyclic acetals, a process for the optical resolution thereof and their use as intermediates for the preparation of (−) 3-(4-phenyl-1-piperazinyl)-1,2-propanediol (levodropropizine) and salts thereof are described herein.

This application is the national phase under 35 U.S.C. § 371 of PCTInternational Application No. PCT/EP01/08305 which has an Internationalfiling date of Jul. 18, 2001, which designated the United States ofAmerica.

The present invention relates to (±)3-(4-phenyl-1-piperazinyl)-1,2-propanediol cyclic acetals, a process fortheir optical resolution and the use thereof as intermediates for thepreparation of (−)3-(4-phenyl-1-piperazinyl)-1,2-propanediol(levodropropizine) and the salts thereof.

More precisely, the invention relates to (±)2,2-substituted-1,3-dioxolanes of formula (1):

wherein:

each of Ra and Rb, which can be the same or different, is hydrogen,C₁-C₆-alkyl, phenyl, or

Ra and Rb taken together with the C atom they are linked to, form anoptionally substituted 4- to 7-membered carbocyclic ring.

Advantageously, in the compounds of the invention of formula (1), Ra andRb are alkyl groups containing less than 6 C atoms. Ra and Rb arepreferably the same; more preferably, Ra and Rb are methyl or ethyl or,together with the C atom they are linked to, form a ring containing 5 to6 carbon atoms.

The invention also relates to the enantiomerically pure monobasic saltsof the 2,2-substituted-1,3-dioxolanes of formula (1) withpharmaceutically acceptable chiral acids such as L-malic, D- andL-tartaric, D- and L-mandelic, L- and D-camphorsulfonic acids.

Examples of particularly preferred compounds of the invention are:

(±) 1,2-cyclopentylidene-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol;

(±) 1,2-cyclohexyliden-3-(4-phenylpiperazin-1-yl)-propane-1,2-diol;

(±) 1,2-(2-propylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol;

(±) 1,2-(3-pentyliden)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol;

S(−)-1,2-cyclohexyliden-3-(4-phenylpiperazin-1-yl)-propane-1,2-diolL-tartrate;

S(−)-1,2-cyclopentylidene-3-(4-phenylpiperazin-1-yl)-propane-1,2-diolL-tartrate.

The compounds of the invention of formula (1) are prepared by reactingphenylpiperazine with a (±)1,2-glyceryl-dioxolane of formula (2):

wherein X is selected from the group consisting of Cl, Br, I and asuitable sulfonic ester (R—SO₃—), R being selected from the groupconsisting of C₁-C₃-alkyl (preferably methyl), trifluoromethyl, phenyl,p-tolyl and p-methoxy phenyl.

Dioxolanes of formula (2) are known compounds and/or can be preparedaccording to known methods.

The sulfonic esters of formula (2) (X=R—SO₃—) are prepared byesterification with an anhydride or with an alkyl- and/or aryl-sulfonicacid chloride of formula (3)R—SO₃H  (3)

of a (±) 2,2-substituted-1,3-dioxolane-4-methanol of formula (4):

wherein Ra and Rb have the meanings defined above.

Compounds of formula (4) are known compounds. Racemates of formula (4)are, in fact, used as substrates for fermentative resolution processes[U.S. Pat. No. 5,190,867 (Mar. 2, 1993)]. The preparation ofdl-isopropylideneglycerol (Merck 12.5232; Beil 19.65) starting fromglycerol is described in Org. Synth. Coll. Vol III.

The 4-halomethyl-dioxolanes of formula (2) wherein X is Cl, Br or I canbe prepared starting from the corresponding sulfonates of formula (2)(X=RSO₃— wherein R is as defined above) by reaction with an alkali oralkaline-earth halide in an inert solvent, selected from the groupconsisting of acetone, methyl ethyl ketone, tetrahydrofuran, dioxane,dimethylsulfoxide, acetonitrile, a C₁-C₄-alcohol and mixtures thereof. Apreferred method for the synthesis of said compounds comprises thedioxolanation of the corresponding 3-halo-1,2-propanediols, as disclosedin EP 0930311 (Jul. 21, 1999). Particularly preferred is3-chloro-propane-1,2-diol; preferred acetalyzing agents areformaldehyde, acetaldehyde and benzaldehyde, acetone, diethyl ketone,benzophenone, cyclohexanone, the acetals and/or enol ethers thereof,such as 2,2-dimethoxypropane, 2,2-dimethoxyethane, 2-methoxy-propene.

Alternatively, dioxolanes of formula (2) (X=Cl or Br) can also beobtained by acetalyzation of epichlorohydrins or epibromohydrins with acycloalkanone according to the processes described for the preparationof (+)2-chloromethyl-1,4-dioxaspiro[4,5]-decane in FR 1522153 or byBlicke F F et al., J.A.C.S, 74, 1735 (1972) and ibidem, 76, 1226 (1954).

The alkylation reaction of phenylpiperazine with a1,2-glyceryl-dioxolane of formula (2) is performed using reactionconditions conventionally used for the conversion of a secondary amineto a tertiary amine, using for each mol of the alkylating agent offormula (2) at least one mol or a slight molar excess ofphenylpiperazine in the presence of at least one mol of a counterbase.The counterbase is used in at least equimolar amounts with respect tothe alkylating agent of formula (2), and is selected from the groupconsisting of finely divided inorganic bases such as alkali oralkaline-earth (Na, K, Mg, Ca) carbonates or bicarbonates or Ca or Mgoxides, or tertiary amines as triethylamine, dimethyl or diethylaniline,aromatic amines as pyridine, picoline and collidine and, if desired, thephenylpiperazine itself which may be subsequently recycled to asubsequent production cycle.

The alkylation reaction can be performed in the hot, optionally in thepresence of inert solvents such as toluene or xylene which, whenoperating under reflux of the solvent, will advantageously reduce thereaction times.

After completion of the alkylation reaction, any insolubles are filteredor centrifuged off, then the organic phases are repeatedly washed withwater to easily remove the impurities and side-products, and the solventis distilled off to obtain in high yields a residue consisting of asubstantially pure 1,3-dioxolane of the invention of formula (1), whichis recovered either by direct crystallization or after salification witha molar equivalent of a carboxylic acid.

Compounds (1) and the salts thereof are suprisingly easy to crystallizefrom the usual solvents: the process of the invention thereforeminimizes any risks of contaminations due to the presence of glycidolsand/or epihalohydrins traces as potential impurities.

The monobasic salts of the compounds of formula (1) are obtained byusing conventional methods such as salification with equimolecularamounts of the desired acid in a suitable solvent and subsequentcrystallization of the resulting salt.

It has been found that the salification of compounds (1) with chiralacids, particularly with L-tartaric acid, is an efficient opticalresolution method to recover the S-enantiomers of compounds (1) in highyields.

Said (S)(−) enantiomers and the salts thereof are useful as antitussiveagents or as intermediates for the synthesis of (−)3-(4-phenyl-1-piperazinyl)-1,2-propanediol (levodropropizine), by hothydrolysis of aqueous solutions of the (−)1,3-dioxolanes of formula (1)catalyzed by a molar excess of a diluted aqueous solution of a mineralacid such as hydrochloric acid, or of a carboxylic acid such as acetic,malonic or citric acids.

The following examples further illustrate the invention.

EXAMPLE 1

A solution of 11.98 g of (±) 2,3-O-(3-pentylidene)-glycerol tosylate inn-butanol (70 mL) is added under strong stirring with 4.5 g of finelydivided sodium carbonate, then with 6 ml of phenylpiperazine. Themixture is refluxed under stirring and reacted at this temperature for20 h. Butanol is then evaporated off under reduced pressure, the residueis taken up with water and repeatedly extracted with ethyl acetate. Thecombined organic phases are dried and filtered, then the solvent isevaporated off under vacuum and the resulting residue is crystallizedfrom aqueous methanol to obtain 8.95 g of (±)1,2-(3-pentyliden)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol, alsonamed 4-phenylpiperazine, 1-(2,2-diethyl-1,3-dioxolan-4-yl-methyl).

EXAMPLE 2

Following the procedure described in Example 1, using (±)2,3-O-(2-propylidene)-glycerol tosylate, (±)1,2-(2-propylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol, alsonamed 4-phenylpiperazine, 1-(2,2-dimethyl-1,3-diossolan-4-yl-methyl), isobtained.

EXAMPLE 3

A solution of 3.28 g of (±) 1,4-dioxaspiro-[4.5]decane-2-methyl chloridein toluene (16 mL) is added under inert gas atmosphere with 5.45 ml ofphenylpiperazine. The mixture is then refluxed to complete the reaction(approximately 8 hours). The reaction mixture is cooled to about 50° C.,added with 10 ml of water and kept under strong stirring for at least 10minutes. The phases are separated, and the organic phase is repeatedlywashed with water. The solvent is evaporated off to obtain a thick oilwhich is dissolved in hot isopropanol (15 mL). The resulting solution isslowly cooled to separate (±)1,2-cyclohexyliden-3-(4-phenylpiperazin-1-yl)propane-1,2-diol as acrystalline solid, m.p. 58-61° C.

¹H NMR δ 7.26 (t, 2H, J=7.4 Hz); δ 6.95 (d, 2H, J=8.9 Hz); δ 6.85 (t,1H), J=7.28 Hz); δ 4.3 (m, 1H, J=6.1 Hz); δ 4.1 (dd, 1H, J₁=8.0 Hz,J₂=6.1 Hz); δ 3.65 (dd, 1H, J₁=8.0, J₂=7.1 Hz); δ 3.2 (t, 4H, J=5.05Hz); δ 2.9÷2.55 (m, 6H); δ 1.7÷1.3 (m, 10H).

EXAMPLE 4

Following the procedure described in Examples 1 and 3, by reacting a1.3-dioxolane selected from the group consisting of:

(±) 1,4-dioxaspiro[4.4]nonane-2-methanol, mesylate;

(±) 1,4-dioxaspiro[4.4]nonane-2-methyl chloride;

(±) 1,4-dioxaspiro[4.5]decane-2-methanol, trifluoromethanesulfonate;

(±) 1,4-dioxaspiro-[4.5]decane-2-methanol, mesylate;

(±) 1,3-dioxolane-4-chloromethyl-2,2-dimethyl;

(±) 1,3-dioxolane-4-bromo-methyl-2,2-dimethyl;

with phenylpiperazine, the following compounds were obtained:

(±) 1,2-cyclopentylidene-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol;

(±) 1,2-cyclohexylidene-3-(4-phenyl-piperazin-1-yl)propane-1,2-diol;

(±) 1,2-(2-propylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol.

EXAMPLE 5

3 g of L-tartaric acid are added under stirring to a solution of (±)1,2-cyclohexylidene-3-(4-phenyl-piperazin-1-yl)propane-1,2-diol (6.32 g)in absolute ethanol (70 ml). The mixture is stirred until completedissolution, then cooled to 5-8° C. 4.05 g of a crystalline solid areobtained, which is recrystallized from absolute ethanol to yield 3.82 gof S(−)-1,2-cyclohexylidene-3-(4-phenyl-piperazin-1-yl)propane-1,2-diolL-tartrate m.p. 131-132° C., [α]_(D)=−9.6° (c=1%; meoh);

¹H NMR δ 7.5 (dd, 2H, J₁=8.7 J₂=7.3); δ 7.2 (m, 3H); δ 4.8 (m, 1H); δ4.4 (s, 2H); δ 4.35 (dd, 1H, J₁=8.9 Hz J₂=6.7 Hz); δ 3.86 (dd, 1H,J₁=8.9 Hz J₂=5.8 Hz); δ 3.6-3.4 (m, 10H); δ 1.8-1.48 (m, 10H).

EXAMPLE 6

A solution of 2.4 g ofS(−)-1,2-cyclohexylidene-3-(4-phenyl-piperazin-1-yl)propane-1,2-diolL-tartrate in water is alkalinized (pH=8) by addition of 2N NaOH, thenexhaustively extracted with ethyl acetate. The combined organic phasesare washed with a 10% monobasic sodium phosphate solution, dried oversodium sulfate and evaporated to dryness, then crystallized fromisopropanol to obtain 1.5 g ofS(−)-1,2-cyclohexylidene-3-(4-phenyl-piperazin-1-yl)propane-1,2-diol,m.p. 63-64° C., [α]_(D)=−7.8° (1% MeOH).

¹H NMR δ7.26 (t, 2H, J=7.4 Hz); δ 6.95 (d, 2H, J=8.9 Hz); δ 6.85 (t, 1H,J=7.28 Hz); δ 4.3 (m, 1H, J=6.1 Hz); δ 4.1 (dd, 1H, J₁=8.0 Hz, J₂=6.1Hz); δ 3.65 (dd, 1H, J₁=8.0, J₂=7.1 Hz); δ 3.2 (t, 4H, J=5.05 Hz); δ2.9÷2.55 (m, 6H); δ 1.7÷1.3 (m, 10H).

EXAMPLE 7

By salification of a 1,3-dioxolane prepared according to the processesof Examples 1-4 with L-tartaric acid and fractional recrystallization ofthe resulting salts, the following compounds were prepared:

S(−)-1,2-cyclopentylidene-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol,L-tartrate;

S(−)-1,2-(2-propylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol,L-tartrate;

S(−)-1,2-(3-pentylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol,L-tartrate;

which where subsequently neutralized according to the process of Example6, to obtain the corresponding free bases.

EXAMPLE 8

A suspension of 2.8 g ofS(−)-1,2-cyclopentylidene-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diolin 70 ml of aqueous acetic acid (10% w/v) is refluxed for 2 h, thenvapor is bubbled therein to distil off cyclopentanone, which isseparated. The aqueous phase is neutralized to pH 7.5 by addition of a10% NaOH solution, then cooled to 5-10° C., to obtain 1.97 g of (−)3-(4-phenyl-piperazin-1-yl)-propanediol m.p. 102-103° C., [α]_(D)=−23.5°(2.8% CH₂Cl₂).

EXAMPLE 9

Alternatively, 0.35 molar equivalents of one of the 1,3-dioxolanederivatives described in Examples 6 and 7,S(−)1,2-(2-propylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol;S(−) 1,2-cyclopentylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol;S(−)-1,2-cyclohexylidene-3-(4-phenyl-piperazin-1-yl)propane-1,2-diol;are added in portions to a 36% hydrochloric acid solution (36 mL) in 45ml of water under stirring; the suspension is heated to 80° C. to obtaina clear solution, which is kept at this temperature for a further 30minutes, then cooled to 20-25° C. and the aqueous phase is repeatedly isextracted with dichloromethane (3×15 ml), then added with n-butanol (0.5l). The diphasic mixture is refluxed to distil the water n-butanolazeotrope, recovering about 300 ml of distillate, then cooled to promotethe crystallization of (−)3-(4-phenyl-piperazin-1-yl)-propanediolhydrochloride (85 g).

A solution of the hydrochloride in 125 ml of water is decolorized byheating at 50° C. with active charcoal (2.2 g) for 15 minutes, filteredthen neutralized by addition of an ammonium hydroxide aqueous solution(30% w/w). After briefly heating to 50° C., crystallization is startedby addition of (−) 3-(4-phenyl-piperazin-1-yl)-propanediol crystals. Thesuspension is left to spontaneously cool, then kept for 2 hours at+2-+4° C., finally filtered to yield 70-72 g of (−)3-(4-phenyl-piperazin-1-yl)-1,2-propanediol.

1. A compound of formula (1)

wherein: each of Ra and Rb, which can be the same or different, ishydrogen, C₁-C₆-alkyl, phenyl, or Ra and Rb taken together with the Catom they are linked to, form a 4- to 7-membered carbocyclic ring, or asalt thereof.
 2. The compound as claimed in claim 1, wherein Ra and Rbare the same.
 3. The compound as claimed in claim 1, wherein each of Raand Rb is methyl or ethyl.
 4. A compound selected from the groupconsisting of: (±)1,2-cyclopentylidene-3-(4-phenyl-piperazin-1yl)-propane-1,2-diol; (±)1,2-cyclohexylidene-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol; (±)1,2-(2-propylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol; (±)1,2-(3-pentylidene)-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diol;S(−)-1,2-cyclohexylidene-3-(4-phenyl-piperazin-1-yl)-propane-1,2-diolL-tartrate; andS(−)-1,2-cyclopentylidene-3-(4-phenyl-piperazirin-1-yl)-propane-1,2-diolL-tartrate.
 5. A process for the preparation of a compound of formula(1):

wherein each of Ra and Rb, which can be the same or different, ishydrogen, C₁-C₆-alkyl, phenyl, or Ra and Rb taken together with the Catom they are linked to, form a 4- to 7-membered carbocyclic ring, andsalts thereof, said method comprising the steps of reactingphenylpiperazine with a (±) 1,2-glyceryl-dioxolane of formula (2):

wherein X is selected from the group consisting of Cl, Br, I and asuitable sulfonic ester (R—SO₃—), R is selected from the groupconsisting of C₁-C₃-alkyl, trifluoromethyl, phenyl, p-tolyl andp-methoxy phenyl, and Ra and Rb have the same meanings as defined above;and recovering the compound of formula (1).
 6. The process as claimed inclaim 5, wherein the reaction is carried out in the presence of a base,using toluene or xylene as solvents.
 7. The process according to claim5, wherein R of the suitable ester of X in formula (2) is methyl.
 8. Theprocess for the optical resolution of the compounds of any one of claims1-4 by salification with L-tartaric acid.
 9. A process for the synthesisof corresponding (S) enantiomers of the compounds of any one of claims1-4 comprising the step of salificating said compounds with a chiralacid.
 10. A process for the synthesis of (−)3-(4-phenyl-1-piperazinyl)-1,2-propanediol wherein the tartaric-acidsalts of a compound of formula (1)

wherein: each of Ra and Rb, which can be the same or different, ishydrogen, C₁-C₆-alkyl, phenyl, or Ra and Rb taken together with the Catom they are linked to, form a 4- to 7-membered carbocyclic ring, andsalts thereof, are optically resolved to recover the S (−)-enantiomerswhich are then subjected to hot hydrolysis catalyzed by a molar excessof a diluted aqueous solution of a mineral acid.
 11. The processaccording to claim 10, wherein the mineral acid is hydrochloric acid,acetic acid, malonic acid or citric acid.
 12. A method for preparing (−)3-(4-phenyl-1-piperazinyl)-1,2-propanediol comprising the steps ofcatalyzing the compounds of any one of claims 1-4 with a molar excess ofa diluted aqueous solution of a mineral acid, and hot hydrolyzing saidaqueous solution.